Immunoconjugates and methods
Inventors
Han, Xiaojun • ORR, SUVI TUULA MARJUKKA • Bunker, Kevin Duane • HUANG, Peter Qinhua • Fischer, Kimberlee
Assignees
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Publication Number
US-12268750-B2
Publication Date
2025-04-08
Expiration Date
Abstract
Immunoconjugates of the Formula (I) include a linking group for linking an antibody targeting ligand (Ab) to a drug (D). Embodiments of such immunoconjugates are useful for delivering the drug to selected cells or tissues, e.g., for the treatment of cancer. Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n (I)
Core Innovation
The disclosure relates to novel anti-ROR1 monoclonal antibodies that specifically bind human receptor tyrosine kinase like orphan receptor 1 (ROR1). The antibodies comprise defined variable heavy chain (VH) and variable light chain (VL) regions with CDR amino acid sequences that bind the ROR1 extracellular domain (ECD), and the document further describes antibody binding across multiple regions of the ROR1 extracellular domain.
The disclosure also provides an antibody-linked immunoconjugate architecture in which an antibody (Ab) is linked to a drug payload (D) through multi-segment linker structures, including formulas such as [S-L1-L2-L3-L4-L5-L6-L7-D]n, Formula (I), Formula (II), and related Formula (III)/(IV) embodiments. The linker is defined through multiple segments between the antibody linking portion and the drug payload, with extensive structural definitions for L1 through L7 and representative structures including Formula (IVa), Formula (IVb), and Formula (IVc).
The compound space includes defined structural variation for Formula (IV), with variable substituents and ring-closure options, explicit exclusions including deruxtecan and exatecan, and representative embodiments within the broader formula framework. The disclosure also refers to anti-ROR1 antibody and anti-HER2 antibody embodiments, a cytotoxic drug moiety D characterized as exatecan, pharmaceutical compositions, and methods for treating cancer.
A development and characterization program is described for antibodies generated using different immunization cohorts that include full-length ECD, an Ig-like domain, and a short human Ig-like sequence. Epitope binning, cross-reactivity against ROR2 and rodent ROR1, internalization kinetics, developability assessment using AC-SINS, and evaluation of ROR1 antibody-drug conjugates with linker/payload combinations are also described.
Claims Coverage
The provided set includes six independent claims directed to antibody or antigen-binding fragment embodiments that specifically bind human receptor tyrosine kinase like orphan receptor 1 (ROR1). The claims define three alternative sequence-defined antibody embodiments using explicit VHCDR and VLCDR amino-acid sequences, with overlapping coverage repeated across the set.
Ror1-specific antibody defined by VHcdr amino-acid sequences
An antibody or antigen-binding fragment thereof that specifically binds human receptor tyrosine kinase like orphan receptor 1 (ROR1), comprising VHCDR1 with SEQ ID NO: 1, VHCDR2 with SEQ ID NO: 2, and VHCDR3 with SEQ ID NO: 3.
Ror1-specific antibody defined by VLcdr amino-acid sequences
An antibody or antigen-binding fragment thereof that specifically binds human receptor tyrosine kinase like orphan receptor 1 (ROR1), comprising VLCDR1 with SEQ ID NO: 8, VLCDR2 with AAS, and VLCDR3 with SEQ ID NO: 10.
Ror1-specific antibody defined by alternative VHcdr amino-acid sequences
An antibody or antigen-binding fragment thereof that specifically binds human receptor tyrosine kinase like orphan receptor 1 (ROR1), comprising VHCDR1 with SEQ ID NO: 15, VHCDR2 with SEQ ID NO: 16, and VHCDR3 with SEQ ID NO: 17.
Ror1-specific antibody defined by alternative VLcdr amino-acid sequences
An antibody or antigen-binding fragment thereof that specifically binds human receptor tyrosine kinase like orphan receptor 1 (ROR1), comprising VLCDR1 with SEQ ID NO: 22, VLCDR2 with DAY, and VLCDR3 with SEQ ID NO: 24.
Ror1-specific antibody defined by third set of VHcdr amino-acid sequences
An antibody or antigen-binding fragment thereof that specifically binds human receptor tyrosine kinase like orphan receptor 1 (ROR1), comprising VHCDR1 with SEQ ID NO: 29, VHCDR2 with SEQ ID NO: 30, and VHCDR3 with SEQ ID NO: 31.
Ror1-specific antibody defined by third set of VLcdr amino-acid sequences
An antibody or antigen-binding fragment thereof that specifically binds human receptor tyrosine kinase like orphan receptor 1 (ROR1), comprising VLCDR1 with SEQ ID NO: 36, VLCDR2 with DAS, and VLCDR3 with SEQ ID NO: 38.
Across the independent claims, coverage is directed to antibodies or antigen-binding fragments that specifically bind human ROR1 with sequence-constrained VH and VL CDR regions. The main inventive limitation is the fixed specification of VHCDR1/VHCDR2/VHCDR3 and VLCDR1/VLCDR2/VLCDR3 by SEQ ID NOs and explicit short amino-acid sequences, defining three distinct sequence-specific antibody embodiments.
Stated Advantages
Cross-reactivity is evaluated against ROR2 and rodent ROR1.
Internalization kinetics are assessed in cellular assays.
Distinct epitopes and partial/blocking relationships are identified by cellular binning and SPR epitope binning.
Developability risk is evaluated using AC-SINS to assess self-interaction.
Cell-binding saturation, affinity, and internalization improvements versus UC961 are described.
A lower affinity of a particular antibody is linked to deeper tumor penetration.
Potency and IC50 results are reported in ROR+ versus ROR− cells.
Documented Applications
The disclosed immunoconjugates and pharmaceutical compositions are stated to be used for cancer treatment.
The invention is positioned for therapeutic use against cancer, with target indication described as cancer/tumor and methods for treating cancer.
The document describes evaluation of ROR1 antibody-drug conjugates with linker/payload combinations.
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